The Fever Read online

  One day a child was born who, despite seeming quite ordinary, held just such a secret weapon inside her genome. Her DNA, like that of the rest of us, comprised millions of chemicals called nucleotides, arranged in elaborate and complex patterns. One of these had been switched out of order. Such switches, rare though they are, generally result in a swift death in utero or soon after. This child was lucky. She survived despite the hidden eccentricity. The nucleotide switch resulted in her blood cells lacking a certain variety of proteins protruding from their surfaces. Functionally speaking, this didn’t make a lick of difference.

  As the child went about her business, mosquitoes flew into the soft wind of her exhalations, attracted by the carbon dioxide and lactic acid. P. vivax slid into the tiny painless wound the mosquitoes had made, and then hid in the girl’s liver, as always, gathering strength for their impending invasion of the red blood cells. But try as they might, the parasites could not hold on to her subtly transformed blood cells. Without those studded proteins—they’ve come to be called Duffy antigens—the mighty P. vivax that infected the girl was rendered toothless. The foiled parasite would have floated in her bloodstream unhitched, unfed, and exposed. Patrolling foot soldiers of the child’s immune system would have neutralized it with ease.

  When P. vivax descended on the girl’s band of hunter-gatherer kin, their gnarled and arthritic bodies would have writhed with fever and chills, while the girl remained healthy. She’d have extricated herself from the carnage, found a mate, and pushed out babies similarly blessed with the gift of smooth red blood cells. In time, she’d have mothered an army of vivax-immune descendants.

  Stepping over the bodies of P. vivax’s earliest human victims, these descendants swept across the continent of Africa like a tide, reaching as far as the Arabian peninsula and the fringes of Central Asia. By about five thousand years ago, the smooth-celled woman’s hegemony was complete, and there wasn’t a single African alive on the continent who wasn’t her descendant (or the descendant of someone similarly endowed with Duffy-less blood cells).36

  With that, vivax malaria’s reign in Africa abruptly ended.

  • • •

  By then, however, both P. malariae and P. vivax had long escaped their cradle in Africa. Malaria-plagued pioneers had walked out of Africa and settled across Asia, the Middle East, and Europe, ferrying P. vivax and P. malariae with them.

  The temperate regions presented yet another mortal challenge for Plasmodium. European Anopheles mosquitoes were larger, more fecund, and stronger fliers than their tropical cousins. This made them better carriers of malaria. But they also hibernated all winter, to survive the continent’s killing frosts. The long hiatuses between blood meals could disrupt the cycle of malaria transmission for good. Plasmodium can’t just linger inside the body of a mosquito for months on end; it can’t hibernate. After a few weeks trapped inside with no escape, it starts to disintegrate.37

  And so vivax malaria evolved another stage in its convoluted life cycle. After entering the liver, the parasite developed the ability to transform into a dormant form called a hypnozoite, which can survive unnoticed inside the human body for months. In this state of arrested development, it waits out the winter. Later, activated by some as-yet-unknown trigger, the hypnozoite awakens, and the parasite restarts its development and its invasion of red blood cells. (The resulting attacks of malaria suffered by the victim are considered relapses, as opposed to new infections.) This adaptation allowed P. vivax to lie low until the bugs started biting again and its blood feasts could resume.38

  We know that P. vivax’s burden must have been costly in Europe and Asia, because genetic mutations that lessened its toll emerged and spread among malaria’s prey, albeit weakening those who carried them. Normally, genes that deform people’s red blood cells impose enough of a disadvantage to their carriers that the gene slowly dies out, and yet in many regions of the world, such deformities persisted and spread. Hemoglobin E, a gene that deforms hemoglobin, slowed P. vivax’s progress in the body. A genetic condition called thalassemia reduced people’s risk of getting sick from P. vivax infection. Another called ovalocytosis makes red blood cells oval and so rigid that they resist invasion by malarial parasites. Thanks to P. vivax, hemoglobin E spread throughout Southeast Asia, thalassemia in the Middle East and Mediterranean, and ovalocytosis through the Pacific region.39

  But vivax malaria, in its post-Africa incarnation, was not a killer. Rather, it enslaved its victims, imposing a constant and unrelenting tax in blood. The convulsions of fever and chills arrived every summer and fall, as soon as the first mosquitoes fed on the blood of an obliviously relapsing carrier of dormant parasites. P. vivax infected the placentas of growing fetuses. Infected babies withered, with stunted immune defenses that rendered them vulnerable to diarrhea and pneumonia. Under the spell of chronic vivax infection, grown men and women weakened to the point that their ambitions drained away and they became anemically prone and wan, just vital enough to make more blood cells available for a later parasitic feed.

  Convulsed by much more dramatic pathogens such as cholera, measles, and smallpox, malaria’s victims may have barely noticed the parasite’s toll.40 The agrarian lifestyle they had come to lead—staying put on their fetid lands, weak from hunger, living together cheek by jowl—favored the spread of infectious diseases of every ilk.

  Unlike the battle between P. vivax and the Duffy gene in Africa, which ended with P. vivax’s retreat, the battle between the hemoglobin-deforming genes and P. vivax in Europe, Asia, and the Pacific region resulted in one of P. vivax’s greatest victories.41 The malaria parasite had created a new kind of mildly hobbled human, one who could withstand its invasions indefinitely.

  Meanwhile, new opportunities arose in Africa.

  For thousands of years after the Duffy gene beat P. vivax out of Africa, the continent probably carried a fairly light burden from malaria. Its nomadic tribes would have encountered malaria-carrying mosquitoes only occasionally. Common ones, such as Anopheles arabienses, lived on Africa’s dry savannahs, and fed mostly on animals, not humans. The Plasmodium malariae parasite hung on, but just barely, as did an even rarer human malaria parasite, Plasmodium ovale.

  But with the formation of the Sahara desert about twenty-five hundred years ago and the spread of Bantu-speaking peoples into the equatorial rain forests of the continent, humankind and mosquitoes collided together in novel ways. The Bantu hacked into the rain forests to grow yams and plaintains, thus transforming those areas. As the trees fell, the chimps and birds disappeared. For the first time, shafts of sunlight reached the rain-forest floor and it became denuded of the thick absorbent layer of humus that once blanketed it. Rainwater collected in puddles on its rutted surface.42

  A new species of Anopheles mosquito emerged to exploit these new ecological conditions, one that constantly, ingeniously, tests out new habits and habitats. Today, of the nearly 500 known species of the Anopheles mosquito, 170 belong to so-called species complexes—mosquitoes that have, for mostly unknown reasons and despite sharing the same habitats, stopped mating with one another. They’re tribes of the same species, living on the same land, who have banned intertribal romance. It’s an absurdity on the face of it, given that mosquitoes by and large live solitary lives. They’re not sociable enough to be so purposely antisocial. And yet, species complexes have formed again and again.

  So it must have been during the early days of the first farm villages in the rain forests of Africa. A tribe of Anopheles colonized the rain-forest villages, laying their eggs in the new, sunny puddles, which were conveniently as free of fishy, larvae-eating predators as the tree holes of the canopy. These mosquitoes developed a taste for the plentiful humans, within easy reach. In time, this mosquito tribe begat a species: Anopheles gambiae. (The malariologists I spoke to pronounced gambiae to rhyme with Bambi.) A. gambiae enjoy the good life.43 Specifically adapted to the world in and around human habitations, they don’t even need a strong proboscis or swift flyin
g skills.

  Unlike anopheline species in other parts of the world, which feed on humans less than half of the time, A. gambiae specialize in humans, rarely if ever extracting a blood meal from anything other than Homo sapiens.44 There would have been very few animals to tempt A. gambiae in these rain-forest villages anyway. The yam and plaintain farmers didn’t keep domesticated animals, as their counterparts in Europe did. For one thing, African mammals were notoriously difficult to tame. For another, the local tsetse fly transmitted deadly sleeping sickness to any cow or horse brought into Central Africa.45

  All of this held great import for the malaria parasite. In almost every other place where it lived, it had to contend with the imperfect carriage of its mosquito vectors. It had to contend with Anopheles species that were fickle in their blood tastes, depositing the human malaria parasite in cows or horses or some other inappropriate creature. It had to contend with mosquitoes that hibernated all winter or died out during inclement weather. It had to contend with mosquitoes that bit only sporadically, thanks to wandering nomads. All of those frustrations were relieved with the arrival of Anopheles gambiae, which would become the most reliable and efficient vector the parasite ever had.

  All Plasmodium had to do to harvest the promise of A. gambiae carriage was subvert the Duffy defense of the locals. Any mutant parasite that could do this would enjoy the most abundant blood feasts ever, the parasitic easy life with no need to suffer through a killing winter, uncertain transport, or annoyingly wandering nomads. Under such conditions, its progeny would sweep through the population.

  With sufficient numbers of malaria parasites hanging on in the margins of the continent, such a mutant parasite did one day emerge, tailored to exploit the rich new conditions. This parasite didn’t rely on a single strategy to attack red blood cells, as did P. vivax. It had multiple invasion strategies, ensuring that its progeny would indeed get their hemoglobin. The mutant begat a tribe that begat a species: Plasmodium falciparum (pronounced fal-SIP-ah-rum), which could infect as much as 80 percent of its victim’s blood, some twenty-four trillion cells, forty times more than its cousin P. vivax could.46

  The P. falciparum parasite doesn’t need to select the weakest red blood cells, as P. vivax and P. malariae do, which prey primarily on young and aging cells, respectively.47 It has novel ways of eluding its victims’ immune system. Once inside a red blood cell, it sends out its progeny clothed in not just one but a multiplicity of disguises. Each contains multiple copies of the genes that control its antigens, the proteins that alert the immune system to launch an attack. The progeny can control the variable expression of these genes, so that when they bombard the body, each cloned parasite looks different to the immune system. Some portion may be recognized and destroyed, but those in the most novel disguises are not, and with the immune system fooled, they are able to burrow into blood cells, victorious.48

  After thousands of years of malarial respite, Plasmodium was back, in its most terrifying, ferocious incarnation of all.

  Plasmodium falciparum’s toll on early rain-forest villages would have been devastating, with both adults and children felled by the dozens, their parasite-infested blood curdled in their veins. We know of the parasite’s bloodshed some four thousand years ago because of the calamitous genetic adaptations that arose and spread.

  A single-point mutation on a single gene turns pliable blood cells into rigid, frozen crescents called sickle cells. A newborn endowed with two copies of this sickle-cell gene, before the advent of modern medicine, would not have survived childhood. But those endowed with a single dose of the sickle-cell gene—the so-called heterozygotes—found themselves with a useful weapon against the scourge that stalked them. When P. falciparum invaded their bloodstreams and started taking down oxygen-sucking hemoglobin, the rising level of unhitched oxygen would trigger a switch. The hemoglobin molecules in their blood cells fused together like two magnets, turning into stiff crescents, and slashing the risk of death from P. falciparum by 90 percent.49

  If two such sickle-cell gene carriers started a family together, the probability of their children being born with the uniformly fatal condition of a double dose of the sickle-cell gene ran to one in four. Even with those terrible odds, the carriers of the sickle-cell gene out-reproduced those without the gene. Plasmodium falciparum was so deadly that it was better to risk a 25 percent probability of a dead child than to forsake the possibility of a weapon against the parasite.50 And so the sickle-cell gene spread throughout the five continents, lurking inside up to 40 percent of the population in parts of Africa, South Asia, and the Middle East to this day, a silent reminder of falciparum malaria’s deadly legacy and the mortal risks that surviving it has required.51

  Humankind devised a few other weapons against P. falciparum. With each bout of fever, our immune systems can arduously prime themselves against yet another of the parasite’s multifarious disguises. The more infections we suffer, the savvier to P. falciparum’s antigenic guises our immune systems become, which allows people with multiple exposures to enjoy a modicum of immunity to the parasite. They still get infected, but with their immune systems restraining the parasites’ numbers to as much as one million times lower than in those not immune, they may not get as sick. They will almost certainly not die.52

  But such immunity occurs only when people are exposed to chronic infection—that is, multiple death-defying encounters with P. falciparum. It is as fleeting as a suntan. After all, malaria parasites reproduce new generations at a rate two hundred times greater than we do. A few months’ respite from the fiery glare of P. falciparum, and whatever immunity to the local parasite had been arduously acquired starts to fade away, canceled out by a new generation of the parasite.53

  As a result, every year, many hundreds of thousands of people must face an invasion by falciparum malaria utterly defenseless. Through happenstance or lack of time, they have not built up any acquired immunity. P. falciparum destroys nearly one million of them every year. First and foremost, it kills the babies.

  Blantyre’s Queen Elizabeth Hospital is a sprawling, dusty complex of squat brick buildings surrounded by loud, traffic-clogged roads. People mill across its grounds, mostly women wearing traditional wraps and silty blouses, carrying swaddled children on their backs, hanging laundry out to dry along the gates. Inside, the hallways are packed with patients clutching tattered health booklets, waiting to be seen by a doctor. The painted turquoise wall is affixed with an orange plastic laundry basket filled with garbage, and a small sign that reads “Osalabvula.” Do not spit. There are no fans, no air-conditioners, and although the unscreened, glass-paned windows are flung open, the air is fetid and still. Roaming down the hallway, one passes through several mild but discernible zones of odor: mold, sweat, urine. Inside the crowded wards a handful of white-coated doctors drag their stools across the floor and lean in to each patient to hear their whispered complaints.

  The pediatric research ward, at the very edge of the hospital complex, consists of two large rooms holding about fifteen wooden raised beds each, a narrow, fluorescent-tube-lit hallway, and some barren, closet-size offices, including Terrie Taylor’s. Unlike the rest of the hospital, with its crowds and smells, the research ward has a certain serenity to it, despite the drumbeat of child deaths that occur within its walls. Most of the young patients here are deathly ill with malaria, and comatose. There is no welter of plastic tubing or beeping machines around them, as one would see in the West. Their small bodies rest on the high beds unadorned. They appear to be simply asleep.

  Under their beds, their mothers and grandmothers have unrolled their thin wraps and are resting on the cool cement floor. When Taylor and her team stride into the ward, the women jump up abruptly, like schoolkids who’ve been sneaking a nap.

  Two-year-old Duke arrived at the hospital on the Friday before I came to Malawi. He’d been visiting relatives living near Blantyre when he suddenly fell terrifyingly ill. His mother and aunt—his father was at home in their
village, two hours north of the city—brought him to Queen Elizabeth Hospital. Duke most likely shared one of the steel-frame beds with another patient, while his family camped out on the hospital grounds so they could bathe him and wash his bedding. They’d have joined the hordes of others forsaking the demands of an unforgiving corn crop back home—Malawi is a nation of subsistence farmers—to provide hospitalized relatives with this basic nursing care. There’s no one else to do it.

  After Duke’s breathing grew labored, he fell into a coma. His muscles started to flex and extend involuntarily into stiff, bizarre positions. It was in this state that Taylor’s team discovered him and rushed him to the research ward.

  While he lay unconscious, they pumped him with anticonvulsants and drew his blood, dabbed a ruby drop on a glass slide. Down the hall, in the sole air-conditioned room in the ward, a lab technician focused a microscope on the slide and spied the lavender, pale-centered spheres of his red blood cells. For each healthy one, there was another that had been invaded and occupied by Plasmodium falciparum.

  Ironically, while the symptoms of severe malaria are alarmingly apparent to the victim’s family, the disease isn’t easy for clinicians to diagnose. The only surefire way Taylor’s team can finger severe malaria is by lifting their comatose charges’ eyelids and spending up to thirty minutes examining the backs of their eyeballs. A normal eyeball is gray and laced with a thin spiderweb of red blood vessels. In a patient in the throes of severe malaria, those vessels are burst, leaving the eyeball speckled with white splotches and red spots. The spidery vessels themselves are pale orange, not red, the parasite having eaten all the hemoglobin.54